Phase II Clinical Trial to Examine the Efficacy and Safety of Dutasteride in Patients With Kennedy's Disease (Spinal and Bulbar Muscular Atrophy)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 57
- 试验地点
- 1
- 主要终点
- Muscle Strength Change From Baseline
研究概览
简要总结
This study will determine if the drug dutasteride can improve weakness, mobility, functioning, nerve function, and quality of life in patients with spinal and bulbar muscular atrophy (SBMA). Patients with this inherited disease have an abnormal androgen receptor protein. The male hormones testosterone and dihydrotestosterone (DHT) bind to this abnormal receptor, causing damage to nerve cells that innervate muscle and leading to weakness. Dutasteride decreases DHT production. Lowering DHT levels may decrease the harmful effects of DHT to the nerves and improve strength in people with SBMA.
Males 18 years of age and older with SBMA who have neurological symptoms and can walk 100 feet (with or without assistive devices) may be eligible for this study. Candidates are screened with a blood test and a review of their medical records and genetic studies.
Participants undergo the following procedures:
- Blood and urine tests, history and physical examination, assessment of muscle strength
- Quality-of-life questionnaire
- Tests to assess functional abilities, such walking up steps, keeping the head up while lying down, and other measures
- Nerve conduction study and motor unit number estimation to assess nerve damage. A probe placed on the skin delivers small electrical impulses and wires taped to the skin record the impulses.
- Quantitative muscle testing to measure strength. The subject pushes and pulls levers attached to a gauge. Strength is recorded by a computer.
- Medication. Participants are divided into two groups. One group is given the study drug, dutasteride; the other receives a placebo (sugar pill). All participants take their assigned medication once a day for 24 months.
- Follow-up evaluations. Every 6 months for 2 years, participants return to NIH to repeat the tests described above to determine the effects of the dutasteride. Nerve and quantitative muscle testing is not done at the 6- and 18-month visits.
- In addition to their follow-up appointments here at the NIH every 6 months, participants will also have blood tests and a physical examination performed after 3, 9, 15 and 21 months of treatment by the patient's local physician.
详细描述
Background:
Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is a slowly progressive, X-linked motor neuron disease for which there is currently no treatment. It is caused by a mutation in the androgen receptor that results in a polyglutamine repeat expansion. Recent animal studies have demonstrated that decreasing endogenous androgen levels leads to functional improvement and increased survival. Studies have also shown that high levels of 5 alpha-reductase, the enzyme that converts testosterone to the more potent dihydrotestosterone (DHT), are present in the ventral spinal cord, while low levels of this enzyme are found within skeletal muscle. Thus, by selectively decreasing levels of DHT with dutasteride, a 5 alpha-reductase inhibitor, it is hypothesized that there will be a selective protection of motor neurons, without the adverse effects of reducing the anabolic effects of androgen on muscle.
Objective:
This will be a phase II, double-blind, placebo-controlled trial examining the safety and efficacy of the 5 alpha-reductase inhibitor dutasteride in inhibiting the progression of neurodegeneration in patients with Kennedy's disease. Natural history data will also be obtained from the placebo control arm.
Study Population:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Genetically confirmed SBMA
- •Neurological symptoms of SBMA
- •Ability to ambulate 100 feet with or without the use of assistive devices
- •Willingness to participate in all aspects of trial design and follow-up
排除标准
- •Age less than 18 years
- •Female sex
- •A history of hypersensitivity to dutasteride or 5 alpha-reductase inhibitors.
- •Exposure to 5 alpha-reductase inhibitors, anti-androgens, testosterone, or steroids in the preceding 6 months
- •Patients who are taking potent cytochrome P450 3A4 (CYP3A4) inhibitors for over 4 weeks
- •Patients with any pre-existing liver disease
- •Alkaline phosphatase, gamma glutamyl transferase, or direct bilirubin greater than 1.5 times the upper limit of normal
- •Alanine aminotransferase or aspartate aminotransferase greater than 1.5 times upper limit of normal in subjects with normal creatine kinase levels
- •Creatinine greater than 1.5 times the upper limit of normal
- •Platelet count, white blood cell count or hemoglobin below the lower limit of normal
- •Other clinically significant medical disease that, in the judgment of the investigators, would expose the patient to undue risk of harm or prevent the patient from completing the study
研究组 & 干预措施
Dutasteride
Dutasteride 0.5 mg/day
干预措施: Dutasteride (Drug)
Placebo
Matched placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Muscle Strength Change From Baseline
时间窗: 0, 12, and 24 months
Quantitative muscle assessment (QMA) was done with a fixed frame dynamometer, a strain gauge tensiometer, and a computer-aided acquisition system. Maximal voluntary isometric muscle contractions were measured twice, the average was calculated, and the results were summed over 22 muscle groups (11 on each side). The total force was scaled for body weight and expressed as percent change from baseline. Measurements were performed at 0, 12, and 24 months. The calculated percent changes at 12 and 24 months are shown.
次要结局
- Creatine Kinase, Change From Baseline(0, 12, and 24 months)
- Manual Muscle Testing, Change From Baseline.(0, 12, and 24 months)
- Adult Myopathy Assessment Tool, Change From Baseline(0, 12, and 24 months)
- Timed 2-minute Walk, Change From Baseline(0, 12, and 24 months)
- Swallow Score Average, Change From Baseline(0, 12, and 24 months)
- Bulbar Rating Scale, Change From Baseline(0, 12, and 24 months)
- Sensory Nerve Action Potential Average, Change From Baseline(0, 12, and 24 months)
- Median Compound Muscle Action Potential, Change From Baseline(0, 12, and 24 months)
- Peroneal Compound Muscle Action Potential, Change From Baseline(0, 12, and 24 months)
- Motor Unit Nerve Estimation, Change From Baseline(0, 12, and 24 months)
- Activities of Daily Living, Change From Baseline(0, 12, and 24 months)
- Medical Outcomes Study 36-item Short Form Version 2 (SF-36v2) Physical Component Summary, Change From Baseline(0, 12, and 24 months)
- Medical Outcomes Study 36-item Short Form Version 2 (SF-36v2) Mental Component Summary, Percent Change From Baseline(0, 12, and 24 months)
- International Index for Erectile Function (IIEF), Change From Baseline(0, 12, and 24 months)